Linda C. Mayes - US grants

We propose a longitudinal study from birth to 24 months of infants exposed to cocaine in utero. The study focuses both on the identifiable short- term, neonatal manifestations of cocaine exposure and on the long-term effects on the infant's state regulatory capacities, regulation of attention, and the development of language and symbolic play. The use of cocaine by pregnant women has increased rapidly in the last five years and more and more fetuses are being exposed in utero. Many reports now document the neurophysiological manifestations of cocaine exposure in the immediate neonatal period, but there is little information about the neurobehavioral development of these infants after the first one to two months. The neuropharmacological effects of cocaine in animals and adults, as well as clinical reports describing attentional impairments exhibited by preschool children exposed to cocaine prenatally, suggest that infants exposed to cocaine in utero may be at continuing and serious risk for central nervous system dysfunction. In the proposed study, infants exposed to cocaine will be compared to infants whose mothers are drug-free. The project is being done in collaboration with an extensive treatment program for cocaine dependent pregnant women in which 300 women will be enrolled over a three year period. We will match the cocaine dependent group to the control group by maternal socioeconomic status, infant sex and birth order, and for a combination of infant birthweight and gestational age. Neonatal assessments of the infants will focus on the neurological organization as measured by the Brazelton Neonatal Behavior Assessment Scales (NBAS) and by the acoustic analysis of the infants' cries. After hospital discharge, infants will be seen at three, six, twelve, eighteen and twenty-four months for sequential assessments of the regulation of attentional states, the capacity to sustain exploration, state organization, adaptive behavior development, language and symbolic play development, and mental age. Additionally, because of the contributions of maternal behavior to the infant outcomes selected, we will examine both the mother's interactive style with her infant particularly in terms of attention directing activities and the intervening maternal variables likely to influence the mother's ability to respond to the infant (psychopathology, life stresses, anxiety and depression, and sense of parenting competence). We will also examine the influence of the substance abuse treatment program on the mothers' capacities to care for their infants. This study has important implications for understanding how the mother's use of cocaine during pregnancy may jeopardize the infant's developing attentional capacities through specific effects on fetal brain development. We expect that information from this longitudinal study will also be useful in designing service programs for such infants.

My application for an RSDA (K02) award reflects a series of steps in my own career development that have brought my work to the study of the behavioral teratology of substance abuse, specifically cocaine, and to the multidisciplinary approach to the study of children growing up in cocaine abusing homes. From the beginning of my career as a research fellow in neonatology and developmental pediatrics and then as a faculty member in the Yale Child Study Center, the focus of my research has been on the developmental outcome of infants and young children at biological and psychosocial risk for developmental impairments. Because I am a pediatrician with additional training in neonatology, developmental pediatrics and psychology, and child psychiatry, I bring to my work and understanding of basic physiological processes in infants, of children's psychological development, and of experimental techniques from developmental psychology. With this award, I plan to enhance my investigative skills and understanding in the particular applications to studies of prenatal cocaine exposure of techniques for studying attentional regulation and the contribution of environmental effects to early attentional and information processing. Specifically, there are five areas of career development relevant to substance abuse that I have planned for the period covered by this award: (1) The study of psychological and psychiatric functioning among cocaine abusing adults particularly in those domains such as attention that may influence their functioning as parents; (2) Studying the regulation of arousal and attention among cocaine-exposed infants and toddlers using a combination of neurobehavioral and physiological assessments; (3) Developing assessment techniques for studying impulsivity and attention among preschool and early school aged children who were exposed to cocaine prenatally and have also been cared for in cocaine using families; (4) Through collaborative projects, integrating neurobehavioral studies in infants with animal models examining both analogous neurobehavioral functions and the ontogeny and function of monoaminergic neurotransmitter systems after prenatal cocaine exposure; and (5) Developing biologic- environment interaction models for how the effects of prenatal cocaine exposure interact with the postnatal cocaine using environment to mediate the child's developmental outcome. My broader interest as I develop my investigative career in the field of substance abuse is to bring a multidisciplinary focus to studies of the effects of pre- and postnatal cocaine exposure on children's functioning. The specific research program proposed in this application is part of NIDA funded R01 project that examines the effects of prenatal cocaine exposure on the infant's and young child's state regulatory capacities, regulation of attention, the development of language and symbolic play, and the contributions of maternal interactive style particularly in terms of attention directing activities. This research and career development program involves collaborations with individuals with a long-standing interest in substance abuse research and is done in the supportive environment of the Yale Child Study Center with its active commitment to clinically informed, multidisciplinary research about basic developmental processes.

We propose a longitudinal study from birth to 24 months of infants exposed to cocaine in utero. The study focuses both on the identifiable short- term, neonatal manifestations of cocaine exposure and on the long-term effects on the infant's state regulatory capacities, regulation of attention, and the development of language and symbolic play. The use of cocaine by pregnant women has increased rapidly in the last five years and more and more fetuses are being exposed in utero. Many reports now document the neurophysiological manifestations of cocaine exposure in the immediate neonatal period, but there is little information about the neurobehavioral development of these infants after the first one to two months. The neuropharmacological effects of cocaine in animals and adults, as well as clinical reports describing attentional impairments exhibited by preschool children exposed to cocaine prenatally, suggest that infants exposed to cocaine in utero may be at continuing and serious risk for central nervous system dysfunction. In the proposed study, infants exposed to cocaine will be compared to infants whose mothers are drug-free. The project is being done in collaboration with an extensive treatment program for cocaine dependent pregnant women in which 300 women will be enrolled over a three year period. We will match the cocaine dependent group to the control group by maternal socioeconomic status, infant sex and birth order, and for a combination of infant birthweight and gestational age. Neonatal assessments of the infants will focus on the neurological organization as measured by the Brazelton Neonatal Behavior Assessment Scales (NBAS) and by the acoustic analysis of the infants' cries. After hospital discharge, infants will be seen at three, six, twelve, eighteen and twenty-four months for sequential assessments of the regulation of attentional states, the capacity to sustain exploration, state organization, adaptive behavior development, language and symbolic play development, and mental age. Additionally, because of the contributions of maternal behavior to the infant outcomes selected, we will examine both the mother's interactive style with her infant particularly in terms of attention directing activities and the intervening maternal variables likely to influence the mother's ability to respond to the infant (psychopathology, life stresses, anxiety and depression, and sense of parenting competence). We will also examine the influence of the substance abuse treatment program on the mothers' capacities to care for their infants. This study has important implications for understanding how the mother's use of cocaine during pregnancy may jeopardize the infant's developing attentional capacities through specific effects on fetal brain development. We expect that information from this longitudinal study will also be useful in designing service programs for such infants.

Methadone and cocaine use during pregnancy may contribute to a more prolonged and potentially more severe neonatal withdrawal course than would be expected with exposure to methadone alone. Length of the withdrawal course and the amount of medication required to manage the infants' withdrawal symptoms will be studied and documented on a daily basis. (This is an ongoing study.)

The studies in this Project concern infants and young children at very high risk for developmental retardation and psychopathology because of their exposure to risk factors during gestation and postnatally. Specifically, we will focus on the interaction between the neurobiological insult of gestational drug exposure and growing up in high risk environments. The use of cocaine by pregnant women (often in combination with alcohol and other drugs) has increased rapidly in the last five years and more fetuses are being exposed. Many reports now document the neurophysiological manifestations of cocaine exposure in the immediate neonatal period, but there is little information about the neuropsychological development of these children after the first one to two months and no studies of attention regulation and rigorously defined aspects of development in preschool aged children. The neuro- pharmacological effects of cocaine in animals and adults, as well as clinical reports describing attentional impairments exhibited by preschool children proposed to cocaine prenatally, suggest that infants exposed to cocaine in utero may be at continuing and various risk for central nervous system dysfunction. The studies in this Project are based on a rigorous, longitudinal investigation from birth to 60 months of children exposed to cocaine in utero. The study focuses on the long-term effects on the regulation of attention and states of arousal, cognitive development, and adaptive behavior. Infants and young children prenatally exposed to cocaine are compared to children whose mothers are cocaine- free and both groups are seen at 3, 6, 12, 18, and 24 months and every 6 months from 30 to 60 months. At these times, repeated measures are done of four variables (arousal regulatory capacities, regulation of attentional states, general developmental competency and adaptive behavior). Additionally, because of the contributions of maternal behavior to children's regulation of attention, mental interactions with the child and examined at each time point. This study has important applications for understanding how impairments in attention and arousal regulation impact cognitive performance, adaptive behavior, and social interaction in the preschool aged child. The emphasis of this Project Area on neurobiological vulnerability and environmental interaction in developmental disorders is closely related to the other Projects in this Program Project. This Project also makes an important contribution to an area of high national concern, the neurobiological and environmental factors involved in the development of children exposed to drugs.

DESCRIPTION: (Applicant's Abstract) This competing continuation seeks to extend an ongoing longitudinal project (RO1 DA-06025) examining relations among prenatal cocaine exposure, postnatal environmental instability, and the cognitive and social development of infants and children from birth to 36 months. The proposed study series aims to extend the follow-up of these children through age 7 years with a particular focus on the regulation of arousal and attention. Because of cocaine's effect on the developing monoaminergic system, prenatal cocaine-exposure may interfere with the developmental ontogeny of the ability to regulate states of arousal and thereby affect the normal development of capacities to regulate attentional states and to respond to stressful events. Inasmuch as the regulation of arousal-modulated attention is crucial to perceptual, cognitive, language, and social development, early disruption in the developmental ontogeny of arousal and attentional regulatory capacities may have effects that extend well into the school-aged years and alter the normal trajectory of cognitive, language, and social-emotional development. In the last 4 years, 411 children (233 prenatally cocaine-exposed and 178 non-cocaine-exposed) now ranging in age from 3 to 48 months have been recruited and maintained. Extensive data have been gathered on the associations of prenatal cocaine (and other drug) exposure with arousal and attention regulatory capacities, and cognitive, language, and adaptive behavior development, and the effects of maternal substance abuse on mother-child interactions. Findings from the first phase of follow-up suggest an association between cocaine exposure and impairments in the regulation of arousal and attentional states and also point to the disruptive effects of substance abuse on the parenting environment. The objective of this competing renewal is to continue through age 7 years, the follow-up of this cohort of cocaine-exposed and non-cocaine-exposed children with repeated assessments of: (1) arousal regulation operationalized behaviorally and neurophysiologically as the startle response and heart rate variability; (2) attention regulation operationalized as the ability to sustain attention, identify stimuli, and inhibit responses; (3) executive function (4) cognitive and language development, (5) adaptive and maladaptive behavior, (6) school achievement (7) social adjustment, (8) the incidence of childhood psychiatric disorders of attention, anxiety, and conduct and (9) social and environmental risks including continued maternal drug use, parental stress and dysfunction, and family disruption. The follow-up continues to build on an interactive model in which children with developmental risks are more or less vulnerable to poor outcomes depending on the severity of their environmental disruption and stress.

DESCRIPTION: (Applicant's Abstract) Through this competing continuation application for an RSDA (K02) award, I seek to extend and deepen a line of work on arousal and attention regulation in prenatally cocaine-exposed children that I have developed with an initial five years of support. In these previous five years, I have developed my line of work along models of neurobehaviorail teratology while continuing a thematic focus dating from earlier in my research career on brain-behavior relations and the regulation of states of arousal. My proposal for the next five years makes full use of the interdisciplinary collaborative opportunities within my own department (the Yale Child Study Center) and with two collaborators in other institutions. I propose to extend my focus on mechanisms of arousal regulation with both new conceptual and methodologic/applied emphases on the neurobiology, neurophysiology, and neuropsychology of arousal regulation in preschool and school age children exposed to biological risks (e.g., prenatal cocaine exposure) and psychosocial adversity. I propose three areas of career development: (1 ) To extend my knowledge regarding neurobiological models of arousal regulation with specific attention to corticostriatal systems and the interface with neuropsychological approaches to prefrontal cortical function, (2) To apply neurophysiologic methods to the study of arousal regulation (e.g., the fear or emotion-potentiated startle response); and (3) To extend my understanding of the neuropsychological assessment of arousal and attention regulation in preschool and school age children. The accompanying research plan is based on an ongoing R01 (DA 06025) now in the seventh year of NIDA funding. The ongoing study examines relations among prenatal cocaine exposure, postnatal environmental instability, and the cognitive and social development of infants and children from birth through 8 years of age. The developmental domains of particular focus are the regulation of arousal and attention. The proposed cohort for study is 442 children (254 prenatally cocaine-exposed and 188 non-cocaine-exposed) who now range in age from 3.5 to 7 years. Children will be seen biyearly between 4 and 8 years with repeated assessments in the following domains: a) arousal regulation operationalized behaviorally as state and emotional reactivity and neurophysiologically as the startle response and heart rate variability; (b) attention regulation operationalized as the ability to sustain attention, identify stimuli, and inhibit responses; (c) aspects of executive functioning (in particular reflective of prefrontal cortex functioning); (d) cognitive function, (e) adaptive and maladaptive behavior, (f) school performance; (9) social adjustment, and (h) the incidence of childhood psychiatric disorders of attention, anxiety, and conduct. Early disruption of the developmental ontogeny of arousal and attentional regulatory capacities may have effects that extend well into the school-aged years and alter the normal trajectory of cognitive and social-emotional development.

The studies in this Project concern infants and young children at very high risk for developmental retardation and psychopathology because of their exposure to risk factors during gestation and postnatally. Specifically, we will focus on the interaction between the neurobiological insult of gestational drug exposure and growing up in high risk environments. The use of cocaine by pregnant women (often in combination with alcohol and other drugs) has increased rapidly in the last five years and more fetuses are being exposed. Many reports now document the neurophysiological manifestations of cocaine exposure in the immediate neonatal period, but there is little information about the neuropsychological development of these children after the first one to two months and no studies of attention regulation and rigorously defined aspects of development in preschool aged children. The neuro- pharmacological effects of cocaine in animals and adults, as well as clinical reports describing attentional impairments exhibited by preschool children proposed to cocaine prenatally, suggest that infants exposed to cocaine in utero may be at continuing and various risk for central nervous system dysfunction. The studies in this Project are based on a rigorous, longitudinal investigation from birth to 60 months of children exposed to cocaine in utero. The study focuses on the long-term effects on the regulation of attention and states of arousal, cognitive development, and adaptive behavior. Infants and young children prenatally exposed to cocaine are compared to children whose mothers are cocaine- free and both groups are seen at 3, 6, 12, 18, and 24 months and every 6 months from 30 to 60 months. At these times, repeated measures are done of four variables (arousal regulatory capacities, regulation of attentional states, general developmental competency and adaptive behavior). Additionally, because of the contributions of maternal behavior to children's regulation of attention, mental interactions with the child and examined at each time point. This study has important applications for understanding how impairments in attention and arousal regulation impact cognitive performance, adaptive behavior, and social interaction in the preschool aged child. The emphasis of this Project Area on neurobiological vulnerability and environmental interaction in developmental disorders is closely related to the other Projects in this Program Project. This Project also makes an important contribution to an area of high national concern, the neurobiological and environmental factors involved in the development of children exposed to drugs.

DESCRIPTION (provided by applicant): This revised competing continuation seeks to extend through 11 years an ongoing longitudinal project (RO1 DA-06025) examining relations among prenatal cocaine exposure, environmental instability, and the neuropsychological development of 369 middle-school-aged children who have been followed longitudinally since birth. Because of cocaine's effect on the developing monoaminergic system, prenatal cocaine-exposure may interfere with the developmental ontogeny of the ability to: regulate states of arousal and attention and thereby affect the normal development of prefrontal cortical executive functions. In the first two phases of study, we have described a continuum of developmental impairment among prenatally cocaine-exposed children that includes emotional lability, impaired visuospatial processing and visual motor integration, delayed cognitive and receptive language development, impulsivity and difficulty inhibiting prepotent responses, attenuated stress response systems, and increased parental dysfunction. In the next phase of study, we propose to follow-up on these findings and assess children exposed prenatally to cocaine and two non-cocaine-exposed comparison groups twice yearly between the ages of 7 and 10 years with convergent measures of the following child-related domains: (1) cognitive and language functioning and academic achievement; (2) attention regulation and other aspects of executive functioning; (3) stress reactivity operationalized as the startle response; (4) adaptive and maladaptive behavior; (5) incidence of childhood psychopathology including early trauma, and (6) physical health and development including early high risk behavior. We will also assess ongoing changes in the child's environment by studying the following parent-related domains: (1) continuing drug use, social disruption, and psychiatric dysfunction; (2) parental stress; and (3) parental functioning. Early disruption of the regulation of arousal-modulated attention and executive functions may have effects that extend well into the school age years and alter the normal trajectory of cognitive, language, and social-emotional development. Additionally, because prenatally cocaine-exposed children often grow up in environmental discord, developmental impairments in these children also likely reflect the interactive effects of both prenatal cocaine exposure and often severe environmental dysfunction. Such interactions place cocaine-exposed children at higher risk for externalizing forms of psychopathology.

DESCRIPTION (provided by applicant): This application is for the purchase of a high-density 256 Channel Geodesic EEG System from Electrical Geodesics, Inc. (EGI). This equipment will be used as a part of the developmental neuroimaging program (DNP) of the Yale University School of Medicine that brings together a multidisciplinary group of investigators interested in basic questions of neural development in children and adults. Nine investigators from the Child Study Center, the Departments of Diagnostic Imaging and Adult Psychiatry, as well as the University of Louisville will be users of this system. An oversight committee from the DNP will regulate access to the system that will be housed in the Child Study Center. The PI has experience with the EGI system through collaboration with investigators at the University of Louisville who have extensively used high-density EEG methods. Each of the investigators who will be users of this equipment are most interested in the EGI system because of two advantages--the high-density cortical mapping that makes possible source localization and the ease with which studies may be done with infants and young children. Several of the planned studies include comparison and/or integration with fMRI. The EGI system permits dense mapping of EEG signals that are time-locked to the onset of an eliciting event--the event related-potential. Although there are a number of facilities at Yale to study event-related potentials, no system currently available at Yale affords the opportunity to obtain data from more than 64 channels. Increasing the number of channels to 256 affords the ability to map more accurately the cortical (or subcortical) source of change in signal in response to the stimulus. Also, no system at Yale currently offers a way to study infants and very young children in ways that minimize both the risk of infection and subject loss during the often-time consuming application of electrodes. The high-density system as developed by EGI affords a practically easy way to apply electrodes in a single net that makes it possible to study very young infants and children in whom fMRI studies are also less feasible because of the difficulties in helping infants and children minimize their motion during the procedure. The high-density mapping capacity is a particularly strong advantage for the EGI system. Source localization is an extremely important area of scientific interest among developmental neuroscientists and neuroimagers. While fMRI affords such a capacity, the event-related potential provides a finer grained level of temporal information (as short as one msec or less) regarding the brain s response to a stimulus and this level of temporal resolution is markedly superior to fMRI. Thus, the capacity for high-density mapping as offered by the EGI system makes possible the ability to create a dynamic neural profile of how an individual processes a given event.

DESCRIPTION (provided by applicant): Because of cocaine's effect on developing monoaminergic systems, prenatal cocaine-exposure may interfere with the developmental ontogeny of children's abilities to regulate states of arousal and attention, thereby altering the development of prefrontal cortical executive functions. The present proposal seeks to extend promising preliminary findings regarding cortical functioning in prenatally cocaine exposed school-aged children participating in event related potential (ERP) studies. Subjects participating in these preliminary studies are members of cohort of 369 children followed longitudinally since birth (RO1 DA-06025) with biyeady visits in which we have described a continuum of developmental impairment among prenatally cocaine-exposed children that includes emotional liability, impaired visuospatial processing and visual motor integration, impulsivity and difficulty inhibiting prepotent responses. The cohort is currently participating in an ongoing 7 to 11 year follow-up with repeated assessments of, among other domains, attention regulation and aspects of executive functioning. In the preliminary ERP studies that are the basis of the present proposal, 29 prenatally prenatally cocaine-exposed and non-cocaine-exposed 7 to 9 year old children responded to a standard Stroop paradigm and a familiarization paradigm. Effects across both experiments were noted in the region of the initial positive peak (P1), the following large negative peak (N1) and the later positive peak (P2). In the Stroop paradigm, cocaine exposed children generated longer latency and prolonged ERP components while the control children produced faster and briefer responses. In the familiarization paradigm, results suggest that cocaine exposed children utilize more cortex to discriminate between repeated presentations of the same stimuli compared to non-cocaine exposed children. Taken together, these findings indicate that early exposure to cocaine may inhibit the specialization and streamlining of brain region involvement during cognitive processing such that task processing is slower to begin, requires more diverse cortical involvement, and requires more time to complete. Based on these findings, we propose to use ERP methods to assess with repeated visits at 11,12, & 13 years the 369 children participating in our longitudinal cohort using three stimulus response experiments, the Stroop, a familiar-novel words paradigm, and a P300 traditional "odd-ball" paradigm. Research utilizing ERP methodology in children has demonstrated its potential in studying frontal maturation, and thus it may provide additional information necessary for clarifying the general and specific effects of prenatal cocaine exposure on cortical functioning and the developmental course of cognitive functions. Such information may then lead to better definition and treatment of these developmental problems.

DESCRIPTION (provided by applicant): This application for a senior scientist award builds on over decade of work on studies of the impact of parental cocaine abuse during pregnancy on children's developing emotional regulatory and executive control functions in a longitudinal cohort of exposed and non-exposed children followed since birth. I have three goals for the period of this senior research award. First, I plan to devote these next five years to further developing and enhancing the newest component of our research laboratory, our high density event related potential lab and the application of this method to studying cortical maturation in cocaine-exposed children. This first goal seeks to extend promising preliminary findings regarding cortical functioning in prenatally cocaine exposed school-aged children participating in event related potential (ERP) studies. In the preliminary ERP studies that are the basis of my scientific plan and of a recently funded NIDA application (RO1 DA17863-01), ERP findings indicate that early exposure to cocaine may inhibit the specialization and streamlining of brain region involvement during cognitive processing such that task processing is slower to begin, requires more diverse cortical involvement, and requires more time to complete. Based on these findings, we propose to use ERP methods to assess with repeated visits at 11,12, & 13 years the 369 children participating in an ongoing longitudinal study (RO1 DA-06025) using three stimulus response experiments, the Stroop, a familiar-novel words paradigm, and a P300 traditional "odd-ball" paradigm. Research utilizing ERP methodology in children has demonstrated its potential in studying frontal maturation, and thus it may provide additional information necessary for clarifying the general and specific effects of prenatal cocaine exposure on cortical functioning and the developmental course of cognitive functions. Such information may then lead to better definition and treatment of these developmental problems. As the second goal of this senior scientist award, I will devote these next five years to developing my expertise in event related potentials as a neuroimaging technique and to designing appropriate paradigms for studying aspects of prefrontal cortical maturation in children from high-risk environments and biological risk conditions. Third, during this next phase of my laboratory development, I will further enhance the opportunities for pre-doctoral and post-doctoral fellows training in behavioral neuroscionce using resources of our high density ERP and neurophysiology laboratories.

DESCRIPTION (provided by applicant): This multidisicplinary proposal focuses on the developmental trajectories of component cognitive abilities within inhibition and executive control functions in preschool to early school aged children living in varying levels of economic disadvantage and advantage. While many studies have shown an association between economic deprivation and impaired cognitive development in childhood, no studies have explored the impact of economic and environmental disadvantage on component neurocognitive capacities within executive control functions. We propose that 1 mechanism for the impact of poverty on cognitive development may be through delays or impaired executive control functions (e.g., working memory, inhibition) and more specifically through an impairment in inhibitory executive control functions. To explore this hypothesis, we bring 5 disciplines together--behavioral neuroscience, neuropsychology, epidemiology, child development, and economics--that represent the expertise of several actively collaborating laboratories with considerable collective experience in studying executive control functions in children and in the application of such studies to high-risk populations. The study sample takes advantage of a unique, time-limited opportunity to follow-up 2 well studied birth cohorts of children, who are from the greater New Haven area and will soon be 4 and 5 years old. We propose to characterize component cognitive abilities within inhibitory executive control functions in boys and girls from 3 income-to-need levels (below poverty, at poverty, and above poverty line) and 3 ethnicity groups (African-American, Hispanic- American and European-American) (a 2 X 3 X 3 design with 360 children total recruited at 2 ages (4 and 5 years) and followed longitudinally through age 8 years. Through growth curve modeling, we will study how these component functions are built up over the course of development from 4 to 8 years, and whether or not these trajectories vary between children growing up in poverty and environmental disadvantage and those not. We will also study how parental behavior, parental beliefs and attitudes, parental mental health, and home environment might moderate relations between economic disadvantage and possible deleterious effects on neurocognitive development. Studying inhibitory processes within executive control functions is particularly pertinent to studies of economically disadvantaged populations in whom a number of developmental delays and/or developmental disorders involving dysregulated inhibition are said to be more common. Having a more detailed understanding of the developmental trajectories of children from low-income samples on basic assessments of inhibitory executive control may inform mechanism questions about how poverty impacts general cognitive capacities.

Because of cocaine's effect on developing monoaminergic systems, prenatal cocaine-exposure may interfere with the developmental ontogeny of children's abilities to regulate states of arousal and attention, thereby altering the development of prefrontal cortical executive functions. The present proposal seeks to extend promising preliminary findings regarding cortical functioning in prenatally cocaine exposed school-aged children participating in event related potential (ERP) studies. Subjects participating in these preliminary studies are members of cohort of 369 children followed longitudinally since birth (RO1 DA-06025) with biyeady visits in which we have described a continuum of developmental impairment among prenatally cocaine-exposed children that includes emotional liability, impaired visuospatial processing and visual motor integration, impulsivity and difficulty inhibiting prepotent responses. The cohort is currently participating in an ongoing 7 to 11 year follow-up with repeated assessments of, among other domains, attention regulation and aspects of executive functioning. In the preliminary ERP studies that are the basis of the present proposal, 29 prenatally prenatally cocaine-exposed and non-cocaine-exposed 7 to 9 year old children responded to a standard Stroop paradigm and a familiarization paradigm. Effects across both experiments were noted in the region of the initial positive peak (P1), the following large negative peak (N1) and the later positive peak (P2). In the Stroop paradigm, cocaine exposed children generated longer latency and prolonged ERP components while the control children produced faster and briefer responses. In the familiarization paradigm, results suggest that cocaine exposed children utilize more cortex to discriminate between repeated presentations of the same stimuli compared to non-cocaine exposed children. Taken together, these findings indicate that early exposure to cocaine may inhibit the specialization and streamlining of brain region involvement during cognitive processing such that task processing is slower to begin, requires more diverse cortical involvement, and requires more time to complete. Based on these findings, we propose to use ERP methods to assess with repeated visits at 11,12, & 13 years the 369 children participating in our longitudinal cohort using three stimulus response experiments, the Stroop, a familiar-novel words paradigm, and a P300 traditional "odd-ball" paradigm. Research utilizing ERP methodology in children has demonstrated its potential in studying frontal maturation, and thus it may provide additional information necessary for clarifying the general and specific effects of prenatal cocaine exposure on cortical functioning and the developmental course of cognitive functions. Such information may then lead to better definition and treatment of these developmental problems.

DESCRIPTION (provided by applicant): Because of cocaine's effect on developing monoaminergic systems, prenatal cocaine-exposure may interfere with the developmental ontogeny of children's abilities to regulate states of arousal and attention, thereby altering the development of prefrontal cortical executive functions. The present proposal seeks to extend promising preliminary findings regarding cortical functioning in prenatally cocaine exposed school-aged children participating in event related potential (ERP) studies. Subjects participating in these preliminary studies are members of cohort of 369 children followed longitudinally since birth (RO1 DA-06025) with biyeady visits in which we have described a continuum of developmental impairment among prenatally cocaine-exposed children that includes emotional liability, impaired visuospatial processing and visual motor integration, impulsivity and difficulty inhibiting prepotent responses. The cohort is currently participating in an ongoing 7 to 11 year follow-up with repeated assessments of, among other domains, attention regulation and aspects of executive functioning. In the preliminary ERP studies that are the basis of the present proposal, 29 prenatally prenatally cocaine-exposed and non-cocaine-exposed 7 to 9 year old children responded to a standard Stroop paradigm and a familiarization paradigm. Effects across both experiments were noted in the region of the initial positive peak (P1), the following large negative peak (N1) and the later positive peak (P2). In the Stroop paradigm, cocaine exposed children generated longer latency and prolonged ERP components while the control children produced faster and briefer responses. In the familiarization paradigm, results suggest that cocaine exposed children utilize more cortex to discriminate between repeated presentations of the same stimuli compared to non-cocaine exposed children. Taken together, these findings indicate that early exposure to cocaine may inhibit the specialization and streamlining of brain region involvement during cognitive processing such that task processing is slower to begin, requires more diverse cortical involvement, and requires more time to complete. Based on these findings, we propose to use ERP methods to assess with repeated visits at 11,12, & 13 years the 369 children participating in our longitudinal cohort using three stimulus response experiments, the Stroop, a familiar-novel words paradigm, and a P300 traditional "odd-ball" paradigm. Research utilizing ERP methodology in children has demonstrated its potential in studying frontal maturation, and thus it may provide additional information necessary for clarifying the general and specific effects of prenatal cocaine exposure on cortical functioning and the developmental course of cognitive functions. Such information may then lead to better definition and treatment of these developmental problems.

This translational, interdisciplinary investigation focuses on the neural circuitry involved in the initiation of early parental care in cocaine-abusing mothers using functional imaging. We focus especially on actively cocaine-dependent women because (1) cocaine abuse is highly correlated with maternal neglect of offspring and poorer maternal-infant interactions in both human and animal models;(2) cocaine addiction co-opts neural circuitry recently shown key to early parenting in both preclinical and human models, that is, dopaminergically regulated limbic-hypothalamic-midbrain brain reward circuits, and (3) parallel studies of cocaine-exposure in the parturient rodent model point to specific disruptions in maternal sensitivity to offspring's cries, olfactory cues, tactile stimulation, and activity patterns such that mothers are more neglectful of their offspring. In this study, 75 cocaine-abusing, 75 non-drug-abusing, and 50 non-cocaine-abusing but other-drug-using, pregnant or recently delivered women will be recruited to participate at 2-4 weeks and 6 months postpartum in a neuroimaging study in which they will listen to cries of known spectral characteristics from cocaine-exposed and non-cocaine-exposed infants and view images of infants 0-6 months in potentially threatening situations. Mothers will rate the intensity of their emotional experience in response to each of the cries and images. At each session, women will be screened for cocaine and tobacco use through urine and serum toxicology. Salivary cortisol, peripheral oxytocin and prolactin levels will be collected pre and post imaging procedure. At 6 months, mothers and infant will participate in a play interaction to examine the relation between parental behavior with the infant and the degree of activation in fear and attachment related circuitry. At two weeks only, cries will be recorded from infants using a standard procedure and analyzed for spectral characteristics, and serum will be obtained from mothers and buccal swabs from infants for DMA extraction and genotyping of relevant polymorphisms identified in preclinical studies as related to parental affiliation (dopamine beta hydroxylase, Fos B, prolactin, and oxytocin). Understanding the neural mechanisms critical to parental investment in infants will facilitate more refined earlier interventions during pregnancy and immediate postpartum period to help substance abusing parents provide sufficient care for their infant despite the compromises they may bring to their parenting role. Earlier and more sustained parental care of infants will also reduce the intergenerational impact of substance abuse on later risk for addiction and related psychopathology among adolescents and young adults.

[unreadable] DESCRIPTION (provided by applicant): Evidence suggests that prenatal exposure to cocaine produces a permanent uncoupling of the dopamine D1 receptor from its G-protein in frontal and cingulate cortices and in caudate nucleus. Activation of D1 receptors during brain development exerts modulatory effects on neuronal development, and prenatal cocaine exposure has been shown to alter neuronal cytoarchitecture in brain regions receiving dopaminergic inputs, including frontal, entorhinal, and piriform cortices. D1 receptors are abundant in frontal cortex and appear to modulate neurocircuits that support the performance of tasks that tap executive functions. Prenatal cocaine exposure has been linked with deficits in executive cognitive capacities, such as allocation of attention, memory, and the ability to suppress processing of and responses to competing stimuli that, in humans, undergo important developmental changes during adolescence. Functional magnetic resonance imaging (fMRI) has demonstrated that performance of executive function tasks is associated with increased activation of fronto-striatal and fronto-parietal networks with increasing age during the adolescent developmental epoch. Event related potential (ERP) studies, have demonstrated consistent maturational changes in ERP morphology, amplitude and latency during performance of attention and executive function tasks. Diffusion tensor imaging (DTI), which provides quantitative measures of white matter microstructure, has demonstrated age related increases in fractional anisotropy, reflecting increases in myelination, in cortical and subcortical white matter pathways that correlate with age related changes in cognitive abilities. This proposal aims to develop and refine fMRI, DTI, and ERP methods for assessing the functional and structural integrity of neurocircuitry supporting selective and divided attention and verbal and visuospatial memory in adolescents with and without prenatal exposure to maternal cocaine use. This work will be performed in collaboration with Linda Mayes, MD, and will form the foundation for future planned projects that will examine the relationship between the integrity of these circuits and cognitive, academic, and psychosocial outcome in a sample of adolescents with and without prenatal exposure to maternal cocaine use that have been followed longitudinally from birth at the Yale Child Study Center (R01 DA-06025, PI: L.C. Mayes). PUBLIC HEALTH RELEVANCE: Children and adolescents with prenatal cocaine exposure have deficits in executive cognitive abilities, including allocation of attention, memory, and the ability to suppress processing of and responses to competing stimuli. This proposal will develop and refine fMRI, DTI, and ERP methods for assessing the function and structure of neurocircuitry supporting selective and divided attention and verbal and visuospatial memory in adolescents with and without prenatal exposure to maternal cocaine use. This work will form the foundation for future planned projects that will examine the relationship between the integrity of these circuits and cognitive, academic, and psychosocial outcome in a sample of adolescents with and without prenatal exposure to maternal cocaine use that have been followed longitudinally from birth at the Yale Child Study Center (R01 DA-06025, PI: L.C. Mayes). [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Despite large-scale public health efforts, the problem of adolescent substance use and emerging dependence continues. To enhance prevention efforts, theorists have sought to understand factors that contribute to the etiology and maintenance of adolescent substance misuse. Several converging theoretical perspectives suggest that the reduction or avoidance of aversive internal states (i.e., negative reinforcement) strongly motivates addictive drug use. Indeed, the adult and adolescent literatures support the role of negative reinforcement processes in both substance use initiation and dependence. Despite the widespread acceptance of negative reinforcement models of substance misuse, the field currently lacks adequate behavioral strategies to assess the complex nature of negative reinforcement processes in humans. Moreover, the neural systems that support negative reinforcement processes have not been well studied in humans. Thus, development of adequate behavioral assessment strategies, especially those informed by neuroimaging considerations, can aid in improving our understanding of the range of processes engaged by the human brain to avoid aversive outcomes. Starting with a well-validated behavioral task that addresses the positive reinforcement aspects of substance use (Balloon Analogue Risk Task, BART), the goal of this R21 application is to develop a parallel version of the task focused on negative reinforcement processes (BART-NR). Moreover, this program of research will address the limitation of behavioral measurement when used alone, in that it is restricted typically to the level of description. To address this issue, we propose the development of the new negative reinforcement BART using high density EEG, with this work setting the stage for future work using fMRI methods. We will begin with a pilot test using 10 participants to develop and refine the methods and procedures for a larger study adequately powered with 145 adolescent subjects, aged between 15 and 17 years, to examine neurophysiological (dense array EEG) factors underlying behavior on our negative reinforcement task. Our approach provides an opportunity to move beyond description into understanding the cumulative influence of positive and negative reinforcement processes underlying adolescent substance use and associated risk behavior. In addition to adding to knowledge at a more basic level, this work also may have more long-range applied implications for the development of more effective and targeted interventions for adolescents at risk for substance use;specifically, those for whom substance use or other risky behaviors serve as a means to reduce aversive negative affect. PUBLIC HEALTH RELEVANCE: Current behavioral tasks focus on the appetitive and positive reinforcement aspects of substance use but largely ignore the crucial parallel processes of negative reinforcement. The goal of this application is to develop a comprehensive behavioral and neurophysiological assessment approach for understanding the role of negative reinforcement in adolescent substance use, with a focus on the current use of EEG methods and longer-term development of an fMRI-appropriate version. In addition to adding to knowledge at a more basic level, this work also may have more long-range applied implications for the development of more effective and targeted interventions for adolescents at risk for substance use;specifically, those for whom substance use or other risky behaviors serve as a means to reduce aversive negative affect.

DESCRIPTION (provided by applicant): The attainment of adequate self-regulation represents a critical developmental milestone that has significant implications for children's social-emotional wellbeing. Prior work has noted the importance of parenting for children's early developing self-regulatory skills, particularly at times in life, such as infancy and early toddlerhood, when children rely heavily on parental support in the regulation of emotion and behavior. Although preliminary evidence suggests that parental self-regulation is important for parenting, most studies have not focused on parenting in early childhood and have not linked parental self-regulation to children's self-regulation through parenting. The aim of the current proposal is to evaluate the effects of multiple aspects of maternal self-regulation (e.g., emotion regulation, effortful control, executive functions, and physiological regulation [heart rate variability]) on parenting of infants and on the emergence of infant self-regulation directly and through parenting. Using a diverse sample (n = 200) of typically developing infants and maternal caregivers recruited from one urban and one rural site, the current proposal evaluates parenting under two conditions. First, the implications of maternal self-regulation for parenting infants in the context of high infant distress is examined using a novel parenting simulation task wherein maternal caregivers interact with a highly distressed, life-like infant simulator. Next, the mother's interactions with her own infant will be evaluated in the context of free play and after a mild infant stressor. Finally, infant self-regulation of emotion during a frustrating task will be examined. It is anticipated that maternal caregivers who have better self-regulation will engage in more adaptive, sensitive parenting behavior during the simulation task as well as with their own infant during play and after a mild stressor. Furthermore, it is expected that parenting will mediate the effects of maternal self-regulation on infant self-regulation. The current study has implications for early developing self-regulatory skills, developmental psychopathology, models of parenting, as well as for parent-infant intervention programs.

DESCRIPTION (provided by applicant): Prenatal cocaine exposure (PCE) can have broad effects on neural development and cognition, with language skills routinely being affected. Extant findings have revealed multiple deficits/delays in language function associated with PCE including: 1) delayed age for language acquisition 2) poorer receptive language 3) poorer expressive language (fewer words spoken) and 4) abnormal response to auditory stimuli. The specific pattern of findings observed indicates language processing deficits at multiple levels from low-level perceptual deficits (e.g., speech processing) to more metacognitive deficits (e.g., semantics, syntax, comprehension). What is unknown is whether these deficits stem from the same or different underlying neurobiological anomalies. Moreover, because extant studies have looked at infants and young children, the extent to which these profiles of language dysfunction change as system demands change, e.g., from phonological development (early childhood) to the understanding of complex semantic and syntactic relationships (late childhood and adolescence), is unknown. It is likely, given the teratogenic effect of PCE, that multiple systems are affected, but also that the observed impairments may differ as a function of changes in system demands associated with development and/or academic pressures. We hypothesize that the perceptual deficits observed are a result of anomalous development of auditory perceptual systems in the temporal lobe and that the higher-level language deficits observed are due to a more diffuse effect on prefrontal lobe function. Additionally, we predict a change in the relative weighting of the affected systems associated with development, which will result in an increase in metacognitve impairment for older children and adolescents. The proposed research will partner with an ongoing longitudinal study of PCE to examine the underlying neurobiology of language processing deficits in a well-characterized behavioral sample of PCE adolescents. Specifically, the goals of the proposed research are 1) to use event related potentials (ERP) to assess the neurocognitive language profiles of PCE adolescents and of control children who were not exposed to cocaine (NCE); 2) to examine the relationship between earlier behavioral performance (measured by standardized tests of language and cognitive skills) and these neurocognitive language profiles; and c) to link these brain-behavior patterns to polymorphisms in candidate genes that have been associated with perceptual or metacognitive skills (COMT and BDNF), in order to establish an endophenotype associated with poor language performance in PCE children. The research outlined in this proposal will have a direct impact our understanding of the relationship between prenatal cocaine exposure and the underlying neurobiology associated with impairments in critical language skills that are important for academic and social success.

DESCRIPTION (provided by applicant): Depressive and anxiety disorders affect women twice as frequently as men. Women are at highest risk for a depressive disorder during their childbearing years. Known risk factors among women include low-income, single marital status, adolescent parenting, and social isolation. Although racial and ethnic minority status, per se, do not increase risk of major depressive disorder, poverty mediates risk of depression leading to high rates of mood disorders in ethnic minority women. Despite their elevated risk for depression, low-income, minority women are less likely to obtain mental health care in either the primary or specialty setting, and less likely to receive appropriate care when they do seek it. Social connections and social support are critical to the mental health of new mothers. However, few interventions have been developed to target social connectedness on a communitywide-level. We propose to promote community-wide maternal mental health through the creation of a web-based social networking application. A sample of mothers residing in New Haven, Connecticut and delivering a baby at Yale-New Haven Hospital will be provided with a web-enabled phone (or smartphone), internet connectivity, access to our web-based community, Momba, and training on how to use it. In years 2 through 3 of the grant period we will randomize women to receive the web-based intervention. A community health worker, termed Community Mental Health Ambassador, will provide training for mothers on how to use the web-based application. To accomplish our aims we have assembled a team of scientists, industry-leaders, and community members to advance not only the science and research, but also the learning and dissemination of information derived from the web-based platform for new mothers. We will manualize and distribute our training curriculum for Community Mental Health Ambassadors for use by communities across the country and internationally. This curriculum will allow communities to train mothers and other outreach and professional staff on the use of technology for the promotion of mental health.

? DESCRIPTION (provided by applicant): Maternal drug addiction constitutes a major public health problem for both women and affected children, with long lasting consequences on children's social, emotional and cognitive development. Current treatment strategies tend to focus on the mother and her current addiction, rather than her relationship with her child, and developmental processes that may perpetuate the addiction problems, such as unresolved childhood attachment trauma, neglect, and chronic stress. Unlike mothers who find engaging with their own infant to be a uniquely rewarding experience, mothers with addictions may be less able to respond appropriately to their infant's cues, finding them less intrinsically rewardin or salient, and more stress provoking. Our current study has identified key areas in dopaminergic and oxytocinergic brain pathways that show a diminished functional MRI response when addicted mothers view the faces of their own vs. unknown infants, compared with non- addicted mothers. These areas include the hypothalamus, striatum and ventromedial prefrontal cortex. Oxytocin, a neuropeptide with decreased peripheral levels seen in addicted mothers, is integrally involved in maternal brain and behavioral responses. When administered intranasally, our pilot data has shown enhanced activation of the striatum, prefrontal cortex and amygdala. The purpose of this renewal grant is to continue and expand upon our investigation of maternal addiction, by conducting a randomized, double-blinded, placebo- controlled, crossover study of intranasal oxytocin on maternal brain responses. A new group of 150 mothers from our two current study sites (Baylor College of Medicine and the Yale Child Study Center) will be enrolled (75 with a history of drug addiction and 75 matched control mothers), along with their 4 to 7-month-old infants, to participate in four study visits over a two-month period. During Visit 1, mothers will complete the Adult Attachment Interview to determine their attachment classification and to identify markers of unresolved trauma. At Visit 2, a videotaped free-play assessment of mother-infant interaction (the CARE-Index), and a modified Still Face Procedure, will be conducted to assess the quality of maternal caregiving and synchrony. During the final two study visits, functional MRI will be used to compare maternal brain responses to infant face cues after receiving either intranasal oxytocin or placebo, comparing own vs. unknown happy and sad faces. We will focus on activation of, and functional connectivity between, the striatum, prefrontal cortex and amygdala, key reward and stress related regions containing oxytocinergic neuronal connections. We will also examine factors that may moderate oxytocin's effect in the brain, including attachment classification, mother-infant synchrony, sensation-seeking or risk-taking behavior, and stress/trauma exposure. This knowledge will contribute significantly to our long-term goal of discovering novel treatment strategies for mothers who suffer from drug dependency and addiction.

Project Summary Child maltreatment is highly prevalent and strongly associated with a range of adverse health outcomes in adults. Multiple human and non-human primate cohorts have collected prospective measures of exposure to child maltreatment and followed participants into adulthood collecting measures of physical and cognitive health. This conference would bring together the leaders of the major longitudinal human and non-human cohorts and experts in measurement and harmonization for a meeting on cross cohort harmonization focused on the relationship of early childhood maltreatment and adult physical and cognitive health. The aims and products of the conference would be: 1) Clear definition and conceptualization of childhood maltreatment that can be studied across cohorts and approaches for uniform recoding of already-collected data and harmonization of measures; 2) Identification of health outcomes and measures that can be used across cohorts as well as a plan for harmonizing measures already used; 3) Articulation of principles for cross species analyses; and 4) Dissemination of resources to provide guidance to investigators in cross cohort analysis of longitudinal data. These aims will advance the field of cross-cohort collaboration to allow attendees to answer key questions in the field about the causal link between early childhood exposure of child maltreatment and later physical and cognitive health outcomes. This work will directly impact the development of intervention efforts to ameliorate the impact of early life exposure to child maltreatment and poor health outcomes across the lifespan.